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Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):328-340. doi: 10.1161/ATVBAHA.116.308507. Epub 2016 Nov 10.

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production.

Author information

1
From the Department of Internal Medicine (Section of Cardiovascular Medicine), VA Connecticut Healthcare System, West Haven (N.C., L.Z., A.H., L.Q., G.T., J.M., R.S., M.M.S., A.R.M.); Department of Medicine and Division of Cardiology, Providence VA Medical Center, RI (A.H., A.R.M.); Department of Internal Medicine (Section of Cardiovascular Medicine), Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (N.C., L.Z., B.D.Y., A.H., S.C., H.V., T.O.Y., K.I., L.Q., L.Q., G.T., K.H., J.M., R.S., H.J.C., M.M.S., J.R.B, A.R.M.); Department of Internal Medicine (Section of Cardiovascular Medicine), Alpert Medical School at Brown University, Providence, RI (A.H., A.R.M.); and Department of Molecular Pathology, Universita Vita Salute School of Medicine, San Raffaele Scientific Institute, Milan, Italy (R.P.).
2
From the Department of Internal Medicine (Section of Cardiovascular Medicine), VA Connecticut Healthcare System, West Haven (N.C., L.Z., A.H., L.Q., G.T., J.M., R.S., M.M.S., A.R.M.); Department of Medicine and Division of Cardiology, Providence VA Medical Center, RI (A.H., A.R.M.); Department of Internal Medicine (Section of Cardiovascular Medicine), Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT (N.C., L.Z., B.D.Y., A.H., S.C., H.V., T.O.Y., K.I., L.Q., L.Q., G.T., K.H., J.M., R.S., H.J.C., M.M.S., J.R.B, A.R.M.); Department of Internal Medicine (Section of Cardiovascular Medicine), Alpert Medical School at Brown University, Providence, RI (A.H., A.R.M.); and Department of Molecular Pathology, Universita Vita Salute School of Medicine, San Raffaele Scientific Institute, Milan, Italy (R.P.). alan_morrison@brown.edu.

Abstract

OBJECTIVE:

The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood.

APPROACH AND RESULTS:

Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1β (IL-1β) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1β expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1β levels. Moreover, we found that elevated IL-1β was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden.

CONCLUSIONS:

Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1β expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

KEYWORDS:

atherosclerosis; biomarkers; coronary artery disease; inflammation; macrophages

PMID:
27834690
PMCID:
PMC5269510
DOI:
10.1161/ATVBAHA.116.308507
[Indexed for MEDLINE]
Free PMC Article

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